The mu-opioid receptor (MOR) is essential for the rewarding and analgesic properties of opiate drugs, such as heroin and morphine. Furthermore, the importance of MOR systems for reward and reinforcement processes, more broadly, are evident from the fact that MOR knockout mice show reduced reward for many different drugs of abuse (nicotine, cocaine, alcohol and cannabinoids) and also for natural rewards such as social interactions and food. A key question that will be addressed in this Component is how MOR subpopulations that are expressed in distinct cell-types and circuits contribute to opioid reinforcement behaviors, specifically self-administration of the opioid receptor agonist, remifentanil. Components I and II have created and fully described genetically modified mice (BACs, knockins and knockouts) that either express MOR only in discrete brain regions (testing sufficiency for addiction behaviors) or mice with deletions of MOR in specific brain areas (testing necessity for addiction behaviors). We will initially determine if there are specific alterations in the acquisition and incubation of remifentanil self-administration as a result of restricted MOR expression. We will test if striatal expression of MOR predominantly confined to the striosome or patch compartment of the striatum is sufficient for opioid addictive behaviors. Conversely, mice that lack MOR in the striatal neurons will be evaluated to test for the necessity of striatal receptors for these same behaviors. We will then focus on the cellular and molecular adaptations within striatal specific cell-types as a consequence of opioid self-administration. Approaches will use optogenetics, electrophysiology and a very novel application of single cell transcriptome analysis developed by Dr. Yi Sun within the E/T-Core. Together this information will provide phenotypic profiles of discrete striatal cell-types (D1 and D2) within specific striatal compartments (ventral/dorsal, striosome/matrix) with the view of identifying novel adaptive mechanisms that could lead to therapeutic strategies for amelioration of drug abuse behaviors.